Insomnia is a condition that affects a person's ability to fall asleep or to maintain sleep. It is the most common sleep disorder, affecting millions of Americans each year. Benzodiazepines, which are available as short, intermediate, or long-acting hypnotic agents, have proven useful in treating insomnia. These benzodiazepines are thought to bind non-selectively to benzodiazepine1 (omega1,) and benzodiazepine2 (omega2) receptors. This non-selective binding may be responsible for some of the potential problems associated with the use of benzodiazepine compounds as hypnotics. For example, some benzodiazepines are thought to interfere with memory, cognition, and psychomotor function. In addition, problems with altered sleep architecture, rebound insomnia, hangover effects, and abuse potential have been reported with benzodiazepine use.
Selective benzodiazepine1 receptor agonists have been developed and studied. For example, zolpidem (Ambien®; Searle and Co.) and zaleplon (Sonata®; Wyeth-Ayerst Co.) are non-benzodiazepine sedative agents thought to selectively bind to benzodiazepine (BZ1) receptors. Zolpidem, an imidazopyridine, has been demonstrated to reduce sleep latency, increase sleep duration, and reduce nighttime awakenings. In addition, zolpidem has been found to preserve stage III and stage IV sleep, and to result in less disruption of REM (Rapid Eye Movement) sleep. Zaleplon is a pyrazolopyrimidine derivative, which has also proven useful as a hypnotic agent. However, zolpidem and zaleplon are both poorly soluble in aqueous media.
Typically, these hypnotic agents are delivered as oral dosages, which are formulated, for example, as tablets or capsules that are swallowed. Oral administration, however, has several disadvantages, such as drug losses during hepatic first pass metabolism, during enzymatic degradation within the GI tract, and during absorption. These drug losses not only increase the variability in drug response, but also often require that the medicament be given in greater initial doses. In addition, because the drug has to pass through the gastrointestinal system in order to enter the blood stream, the time to reach a therapeutic effect may be quite long, typically around forty-five minutes or longer.
Accordingly, other routes of drug administration have been investigated, including those involving transport across the mucous membranes. Of the various mucous membranes (e.g., oral, rectal, vaginal, ocular, nasal, etc.), drug delivery via the mucous membranes in the oral cavity seems to be the most easily tolerated by patients. In addition to avoiding the problems with traditional oral administration, drug delivery via the mucous membranes of the oral cavity has certain other advantages, due to the properties of the oral mucosa itself. For example, the mucous membranes of the oral cavity are highly vascularized and well supplied with lymphatic drainage sites.
In general, the mucous membranes of the oral cavity can be divided into five main regions: the floor of the mouth (sublingual), the cheeks (buccal), the gums (gingival), the roof of the mouth (palatal), and the lining of the lips. These regions differ from each other with respect to their anatomy, drug permeability, and physiological response to drugs. For example, in terms of permeability, sublingual is more permeable than buccal, which is more permeable than palatal. This permeability is generally based on the relative thickness and degree of keratinization of these membranes, with the sublingual mucosa being relatively thin and non-keratinized, the buccal mucosa being thicker and non-keratinized, and the palatal mucosa being intermediate in thickness, but keratinized.
In addition to the differences in permeability of the various mucous membranes, the extent of drug delivery is also affected by the properties of the drug to be delivered. The ability of a molecule to pass through any mucous membrane is dependent upon its size, its lipid solubility, and the extent to which it is ionized, among other factors.
The extent to which a drug is ionized has further been investigated with respect to drug delivery across the mucous membranes. Ionization is dependent on the dissociation constant (pKa), and the pH of the molecule's surrounding environment. In its un-ionized form, a drug is sufficiently lipophilic to traverse a membrane via passive diffusion. In fact, according to the pH partition hypothesis, only un-ionized, non-polar drugs will penetrate a lipid membrane.
At equilibrium, the concentrations of the un-ionized form of the drug are equal on both sides of the membrane. As the concentration gradient drives passive diffusion, an increase in the percentage of the un-ionized form of a drug correspondingly increases the transmucosal absorption of the drug. Maximum absorption across the membrane is thought to occur when a drug is 100% in its un-ionized form. Similarly, absorption across the membrane decreases as the extent of ionization increases. Therefore, one may influence the extent of drug absorption across the mucous membranes of the oral cavity by altering the salivary pH.
Some of the known transmucosal dosage forms include the use of a single buffering agent in order to change the pH of the saliva and tissues surrounding the buccal mucosa. However, these single buffering agents typically react with an acid or a base to create a final pH that is dependent upon the initial pH of the saliva of the user. A buffering agent used to attain a final pH that is dependent upon the initial pH of the user results in great variability. The extent of ionization, and hence the extent of absorption across the mucous membranes cannot be predicted with any sort of accuracy. This may pose significant problems when calculating precise doses, minimizing variability in patient response, and proving consistency in drug loading to the regulatory authorities. In addition, a single buffering agent is typically not capable of sustaining a given pH over a period of time for optimal absorption. While others in the art have disclosed the use of more than one buffering agent, these aforementioned problems are not easily cured by the nonchalant addition of an extra buffering agent, which may be unsafe and cause irreversible damage to the mucous membranes of the oral cavity. As such, a buffering system capable of achieving and sustaining a final pH independent of the initial pH in order to increase transmucosal absorption has not heretofore been demonstrated.
Similarly, a buffer system that facilitates substantially complete conversion of the ionized form of a drug to the un-ionized form in the shortest period of time, which is critical for producing rapid delivery of practically an entire drug dose across the oral mucosa, has not heretofore been demonstrated. Previous dosage forms resulted in great variability in drug delivery, due to the variability in the rates in which a drug was released from its carrier. That is, the rates of drug release in previously described chewing gums or lozenges are largely dependent upon the rate of chewing or sucking of the user. The variability in these rates from user to user further exacerbates the ability to predict the final amount of drug that will enter systemic circulation. In addition, the rate of drug release from the carrier is further dependent upon the ability of the drug to be released therefrom. Often times, the carrier (e.g., gum base) strongly adheres to the drug, making portions of the drug unavailable for absorption.
Accordingly, there is a need in the art for compositions for delivering hypnotic agents across the oral mucosa having buffer systems that facilitate absorption of the agents in a safe and stable manner. Similarly, there is a need in the art for compositions for delivering hypnotic agents across the oral mucosa having a buffer system that produces a final pH, independent of the initial pH, and sustains that final pH for a given period of time. In addition, there is a need in the art for compositions capable of rapidly facilitating substantially complete conversion of the hypnotic agent from its ionized to its un-ionized form. The present invention satisfies these and other needs.